Carbohydrate Metabolism and the Liver: Actual Aspects from Physiology and Disease

Zusammenfassung

Die Leber spielt eine Hauptrolle in der Aufrechterhaltung des Blutglukosespiegels innerhalb eines Normalbereiches. Dies wird durch ein in den Hepatozyten lokalisiertes System aus Enzymen gewährleistet, das für den Glukoseabbau bzw. für die Glukosesynthese verantwortlich ist. Die Steuerung dieses Systems erfolgt durch Mediatoren und Hormone, von denen Insulin eine Schlüsselrolle innehat. Beim Typ-2-Diabetes, aber auch bei verschiedenen Lebererkrankungen kommt es zu eine Störung des hepatischen Glukosestoffwechsels, die durch eine vermehrte hepatische Nüchtern-Glukoseproduktion und eine verminderte Glukoseaufnahme in der Postprandialphase gekennzeichnet ist. Als zentrales pathophysiologisches Element hierbei ist eine Insulinresistenz anzusehen. Die genaue Kenntnis der physiologischen Glukosehomeostase als auch der Mechanismen, die zu einer Insulinresistenz führen, sind entscheidende Vorraussetzung zur Entwicklung neuer Therapieansätze beim Diabetes mellitus wie auch bei Lebererkrankungen, die mit einer Insulinresistenz assoziiert sind. Experimente an genetisch manipulierten Mäusen haben in den letzten Jahren wesentlich zum Verständnis des Kohlenhydratstoffwechsels und seiner Störungen beigetragen. So konnten eine Reihe von Enzymen, Transkriptionsfaktoren und Mediatoren identifiziert werden, die von wesentlicher Bedeutung für die Aufrechterhaltung der hepatischen Glukosehomeostase sind. Zudem bieten solche Mäuse die Möglichkeit, den Glukosestoffwechsel an Modellen von Lebererkrankungen zu erforschen. In der folgenden Übersicht werden daher einige Mausmodelle vorgestellt und im Kontext mit der Situation beim Menschen diskutiert, bei denen durch genetische Manipulation Enzyme der Glukoneogenese, hepatische Transkriptionsfaktoren, IGF-1, hepatische Insulinrezeptoren, Adipokine oder Hepatitis C core Antigen über- bzw. vermindert exprimiert wurden.

Abstract

The liver plays a unique role in controlling carbohydrate metabolism by maintaining glucose concentrations in a normal range. This is achieved by a tightly regulated system of enzymes and kinases regulating either glucose breakdown or synthesis in hepatocytes. This process is under the control of glucoregulatory mediators among which insulin plays a key role. In type 2 diabetes, as well as in liver disease, alterations in hepatic glucose metabolism like an increased post-absorptive glucose production together with diminished glucose uptake following carbohydrate ingestion occur, implying insulin resistance as a central pathological principle. Knowledge of the processes involved in maintaining glucose homeostasis as well as insulin resistance is a prerequisite to develop new therapeutic approaches in diabetes as well as in liver disease. In the recent years, genetically-altered mouse models that have helped to identify enzymes, transcription factors and mediators that are essential for maintaining glucose homeostasis in the liver and provide a valuable tool to study carbohydrate metabolism in liver disease. In this current review, genetically manipulated animals either overexpressing or lacking key gluconeogenic enzymes, hepatic transcription factors, IGF-1, hepatic insulin receptors, adipokines and hepatitis C core antigen will be discussed in the context of human disease.

hepatischer Glukosestoffwechsel - Insulin - IGF-1 - Insulinresistenz - NAFLD - Hepatitis C - hepatogenische Diabetes

hepatic glucose production - insulin - IGF-1 - insulin resistance - NAFLD - hepatitis C - hepatogenous diabetes

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